Diosmin and Hesperidin Have a Protective Effect in Diabetic Neuropathy via the FGF21 and Galectin-3 Pathway.

Background and Objectives: This study aimed to investigate the protective effect of diosmin and hesperidin in diabetic neuropathy using a rat model, focusing on their impact on nerve regeneration through the fibroblast growth factor 21 (FGF21) and galectin-3 (gal3) pathway. Materials and Methods: Forty adult male Wistar rats were used in this study. Diabetes was induced using streptozotocin (STZ), and the rats were divided into control, diabetes and saline-treated, diabetes and diosmin + hesperidin (150 mg/kg) treated, and diabetes and diosmin + hesperidin (300 mg/kg) treated groups. Electromyography (EMG) and inclined plane testing were performed to assess nerve function and motor performance. Sciatic nerve sections were examined histopathologically. Plasma levels of FGF21, galectin-3, and malondialdehyde (MDA) were measured as markers of oxidative stress and inflammation. Results: Diabetic rats treated with saline displayed reduced nerve conduction parameters and impaired motor performance compared to controls. Treatment with diosmin and hesperidin significantly improved compound muscle action potential (CMAP) amplitude, distal latency, and motor performance in a dose-dependent manner. Histopathological examination revealed decreased perineural thickness in treated groups. Additionally, treatment with diosmin and hesperidin resulted in increased plasma FGF21 levels and reduced plasma levels of galectin-3 and MDA, indicating decreased oxidative stress and inflammation. Conclusions: Diosmin and hesperidin exhibited protective effects in diabetic neuropathy by promoting nerve regeneration, enhancing nerve conduction, and improving motor performance. These effects were associated with modulation of the FGF21 and galectin-3 pathway. These findings suggest that diosmin and hesperidin may hold potential as adjunctive therapies for diabetic neuropathy.

Computational Analysis and Experimental Data Exploring the Role of Hesperetin in Ameliorating ADHD and SIRT1/Nrf2/Keap1/OH-1 Signaling.

Attention deficit hyperactivity disorder (ADHD) manifests as poor attention, hyperactivity, as well as impulsive behaviors. Hesperetin (HSP) is a citrus flavanone with strong antioxidant and anti-inflammatory activities. The present study aimed to test hesperetin efficacy in alleviating experimental ADHD in mice and its influence on hippocampal neuron integrity and sirtuin 1 (SIRT1) signaling. An in silico study was performed to test the related proteins. Groups of mice were assigned as control, ADHD model, ADHD/HSP (25 mg/kg), and ADHD/HSP (50 mg/kg). ADHD was induced by feeding with monosodium glutamate (0.4 g/kg, for 8 weeks) and assessed by measuring the motor and attentive behaviors (open filed test, Y-maze test, and marble burying test), histopathological examination of the whole brain tissues, and estimation of inflammatory markers. The in-silico results indicated the putative effects of hesperetin on ADHD by allowing the integration and analysis of large-scale genomic, transcriptomic, and proteomic data. The in vivo results showed that ADHD model mice displayed motor hyperactivity and poor attention in the behavioral tasks and shrank neurons at various hippocampal regions. Further, there was a decline in the mRNA expression and protein levels for SIRT1, the erythroid 2-related factor-2 (Nrf2), kelch like ECH associated protein 1 (Keap1) and hemeoxygenase-1 (OH-1) proteins. Treatment with HSP normalized the motor and attentive behaviors, prevented hippocampal neuron shrinkage, and upregulated SIRT1/Nrf2/Keap1/OH-1 proteins. Taken together, HSP mainly acts by its antioxidant potential. However, therapeutic interventions with hesperetin or a hesperetin-rich diet can be suggested as a complementary treatment in ADHD patients but cannot be suggested as an ADHD treatment per se as it is a heterogeneous and complex disease.

Exploring the Effects and Potential Mechanisms of Hesperidin for the Treatment of CPT-11-Induced Diarrhea: Network Pharmacology, Molecular Docking, and Experimental Validation.

Chemotherapy-induced diarrhea (CID) is a potentially serious side effect that often occurs during anticancer therapy and is caused by the toxic effects of chemotherapeutic drugs on the gastrointestinal tract, resulting in increased frequency of bowel movements and fluid contents. Among these agents, irinotecan (CPT-11) is most commonly associated with CID. Hesperidin (HPD), a flavonoid glycoside found predominantly in citrus fruits, has anti-oxidation properties and anti-inflammation properties that may benefit CID management. Nevertheless, its potential mechanism is still uncertain. In this study, we firstly evaluated the pharmacodynamics of HPD for the treatment of CID in a mouse model, then used network pharmacology and molecular docking methods to excavate the mechanism of HPD in relieving CID, and finally further proved the predicted mechanism through molecular biology experiments. The results demonstrate that HPD significantly alleviated diarrhea, weight loss, colonic pathological damage, oxidative stress, and inflammation in CID mice. In addition, 74 potential targets for HPD intervention in CID were verified by network pharmacology, with the top 10 key targets being AKT1, CASP3, ALB, EGFR, HSP90AA1, MMP9, ESR1, ANXA5, PPARG, and IGF1. The Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis revealed that the PI3K-Akt pathway, FoxO pathway, MAPK pathway, TNF pathway, and Ras pathway were most relevant to the HPD potential treatment of CID genes. The molecular docking results showed that HPD had good binding to seven apoptosis-related targets, including AKT1, ANXA5, CASP3, HSP90AA1, IGF1, MMP9, and PPARG. Moreover, we verified apoptosis by TdT-mediated dUTP nick-end labeling (TUNEL) staining and immunohistochemistry, and the hypothesis about the proteins above was further verified by Western blotting in vivo experiments. Overall, this study elucidates the potential and underlying mechanisms of HPD in alleviating CID.

Hesperidin PLGA nanoparticles potentiate the efficacy of aPD-1 in treating triple negative breast cancer by regulating CCL2 and ADPN expression in cancer-associated adipocytes.

Triple negative breast cancer (TNBC) represents a heterogeneous subtype of breast cancer characterized by an unfavorable prognosis due to its aggressive biology. Cancer-associated adipocytes (CAAs) play an active role in tumor development, invasion and metastasis, and response to treatment by secreting various cytokines. CAAs secrete CCL2 and ADPN which significantly affect the efficacy of aPD-1 in treating breast cancer. Our recent research has demonstrated that Hesperidin, a natural phenolic compound, significantly inhibits CCL2, elevates ADPN secreted by CAAs in vitro and in vivo, remodels the immune microenvironment, and potentiates the efficacy of aPD-1 in triple-negative breast cancer. We used Oil red staining, Bodipy 493/503 staining and quantitative real-time PCR to verify the formation of CAAs. ELISA was used to detect levels of CCL2, ADPN secreted by CAAs. Changes in the number of immune cells in mouse tumor tissues were detected using flow cytometry and immunofluorescence. Our data suggest that Hesperidin PLGA nanoparticles significantly reduced CCL2 and increased ADPN secreted by CAAs, which concurrently decreased the recruitment of M2 macrophages, Tregs and MDSCs while increased the infiltration of CD8+T cells, M1 macrophages and DCs into tumor, thus significantly potentiated the efficacy of aPD-1 in vivo. This study provides a new combined strategy for the clinical treatment of triple-negative breast cancer by interfering with CCL2, ADPN secreted by CAAs to enhance the efficacy of immunotherapy.

Rhein and hesperidin nanoparticles remodel tumor immune microenvironment by reducing CAFs and CCL2 secreted by CAAs for efficient triple-negative breast cancer therapy.

In triple-negative breast cancer (TNBC), the tumor immune microenvironment (TIME) is a highly heterogeneous ecosystem that exerts indispensable roles in tumorigenesis and tumor progression. Cancer-associated fibroblasts (CAFs) and cancer-associated adipocytes (CAAs) are the main matrix components in the TIME of TNBC. CAFs mediate the edesmoplastic response, which is a major driver of the immunosuppressive microenvironment to promote tumor growth. In addition, CAAs, a type of tumor-educated adipocyte, participate in crosstalk with breast cancer and are capable of secreting various cytokines, adipokines and chemokines, especially C-C Motif Chemokine Ligand 2 (CCL2), resulting in changes of cancer cell phenotype and function. Therefore, how to treat tumors by regulating the CAFs and the secretion of CCL2 by CAAs in TIME is investigated here. Our research group previously found that rhein (Rhe) has been identified as effective against CAFs, while hesperidin (Hes) could effectively diminish CCL2 secretion by CAAs. Inspired by the above, we developed unique PLGA-based nanoparticles loaded with Rhe and Hes (RH-NP) using the emulsion solvent diffusion method. The RH-NP particles have an average size of 114.1 ± 0.98 nm. RH-NP effectively reduces CAFs and inhibits CCL2 secretion by CAAs, promoting increased infiltration of cytotoxic T cells and reducing immunosuppressive cell presence within tumors. This innovative, safe, low-toxic, and highly effective anti-tumor strategy could be prospective in TNBC treatment.

Hesperidin Alleviates Hepatic Injury Caused by Deoxynivalenol Exposure through Activation of mTOR and AKT/GSK3ß/TFEB Pathways.

Deoxynivalenol (DON) is a common agricultural mycotoxin that is chemically stable and not easily removed from cereal foods. When organisms consume food made from contaminated crops, it can be hazardous to their health. Numerous studies in recent years have found that hesperidin (HDN) has hepatoprotective effects on a wide range of toxins. However, few scholars have explored the potential of HDN in attenuating DON-induced liver injury. In this study, we established a low-dose DON exposure model and intervened with three doses of HDN, acting on male C57 BL/6 mice and AML12 cells, which served as in vivo and in vitro models, respectively, to investigate the protective mechanism of HDN against DON exposure-induced liver injury. The results suggested that DON disrupted hepatic autophagic fluxes, thereby impairing liver structure and function, and HDN significantly attenuated these changes. Further studies revealed that HDN alleviated DON-induced excessive autophagy through the mTOR pathway and DON-induced lysosomal dysfunction through the AKT/GSK3ß/TFEB pathway. Overall, our study suggested that HDN could ameliorate DON-induced autophagy flux disorders via the mTOR pathway and the AKT/GSK3ß/TFEB pathway, thereby reducing liver injury.

The effect of a flavonoid mixture containing diosmin, hesperidin and troxerutin in women with congestion syndrome associated to pelvic pain: a color Doppler ultrasonography study.

BACKGROUND: Pelvic congestion syndrome (PCS) is associated with chronic pelvic pain (CPP). The efficacy of flavonoids for treating PCS symptoms is still a matter of debate, and little has been published. The aim of this study was to assess the efficacy of a mixture of diosmin, troxerutin, and hesperidin in improving symptoms of patients with PCS, observing a direct effect on circulation by specific color Doppler ultrasonography (CDU) evaluations. METHODS: This was a pilot, prospective, independent, cross-over, daily-diary-based trial. Women were evaluated with CDU for 3 times (baseline, 60 days, 120 days). Data about N.=13 women who completed the study were analyzed. RESULTS: During the treatment, we recorded a significant reduction of intermenstrual and menstrual pain intensity (total points) (P<0.05). The satisfaction after treatment was significantly higher than after placebo (P<0.0001). A significant reduction in the diameter of the major ovarian vein (P=0.004 compared to placebo), associated with an increase in peak systolic velocity (P=0.01) and a corresponding significant increase in the Resistivity Index (P<0.0001) were recorded during treatment. CONCLUSIONS: The use of a mixture of diosmin, troxerutin and hesperidin in women with PCS can significantly help to manage typical symptoms of pelvic pain and it is associated with an evident Doppler effect on pelvic microcirculation.

Hesperidin, a Potential Antiviral Agent against SARS-CoV-2: The Influence of Citrus Consumption on COVID-19 Incidence and Severity in China.

This review examines hesperidin, a citrus bioflavonoid, as a potential antiviral agent against SARS-CoV-2. The COVID-19 pandemic has demanded an urgent need to search for effective antiviral compounds, including those of natural origin, such as hesperidin. The review provides a comprehensive analysis of the chemical properties, bioavailability and antiviral mechanisms of hesperidin, particularly its potential efficacy against SARS-CoV-2. A review of databases, including PubMedPico, Scopus and Web of Science, was conducted using specific keywords and search criteria in accordance with PRISMA (Re-porting Items for Systematic Reviews and Meta-Analysis) guidelines between 2020 and 2024. Of the 207 articles, 37 were selected for the review. A key aspect is the correlation of in vitro, in silico and clinical studies on the antiviral effects of hesperidin with epidemiological data on citrus consumption in China during 2020-2024. The importance of integrating laboratory findings with actual consumption patterns to better understand the role of hesperidin in mitigating COVID-19 was highlighted, and an attempt was made to analyze epidemiological studies to examine the association between citrus juice consumption as a source of hesperidin and the incidence and severity of COVID-19 using China as an example. The review identifies consistencies and discrepancies between experimental and epidemiological data, highlighting the need to correlate the two fields to better understand the potential of hesperidin as an agent against SARS-CoV-2. Challenges and limitations in interpreting the results and future research perspectives in this area are discussed. The aim of this comprehensive review is to bridge the gap between experimental studies and epidemiological evidence and to contribute to the understanding of their correlation.

The effectiveness of hesperidin on bisphenol A-induced spinal cord toxicity in a diabetic rat model.

The potential health risks of bisphenol A (BS) and diabetes (DI) has sparked public concern due to be ubiquitous worldwide. The purpose of this study was to investigate the detrimental impact of BS (200 mg/kg) on the spinal cord tissue in a rat diabetic model. We also evaluated the antioxidant capacity of hesperidin (HS) (100 mg/kg) on spinal cord in BS-treated diabetic rat. Seventy male Wistar albino rats, weighing 180-230 g and 8 weeks old, were randomly chosen, and assigned into seven groups of 10 rats: Control (KON), BS, DI, BS + DI, HS + BS, HS + DI, HS + BS + DI. At the end of the 14-day experimental period, all samples were examined using stereological, biochemical, and histopathological techniques. Our biochemical findings revealed that the SOD level was significantly lower in the BS, DI, and BS + DI groups compared to the KON group (p < 0.05). Compared to the KON group, there was a significant decrease in the number of motor neurons and an increase in the mean volume of central canals in the BS, DI, and BS + DI groups (p < 0.05). In the HS + BC group than the BS group and in the HS + DI group than the DI group, SOD activity and the number of motor neurons were significantly higher; also, the mean volume of spinal central canal was significantly lower (p < 0.05). The novel findings gathered from the histopathological assessment supported our quantitative results. Our speculation was that the exposure to BS and DI was the main cause of neurological alteration in the spinal cord tissues. The administration of HS had the therapeutic potential to mitigate spinal cord abnormalities resulting from BS and DI. However, HS supplementation did not alleviate spinal cord complications in BS-treated diabetic rats.

Cyclosporine-induced kidney damage was halted by sitagliptin and hesperidin via increasing Nrf2 and suppressing TNF-α, NF-κB, and Bax.

Cyclosporine A (CsA) is employed for organ transplantation and autoimmune disorders. Nephrotoxicity is a serious side effect that hampers the therapeutic use of CsA. Hesperidin and sitagliptin were investigated for their antioxidant, anti-inflammatory, and tissue-protective properties. We aimed to investigate and compare the possible nephroprotective effects of hesperidin and sitagliptin. Male Wistar rats were utilized for induction of CsA nephrotoxicity (20 mg/kg/day, intraperitoneally for 7 days). Animals were treated with sitagliptin (10 mg/kg/day, orally for 14 days) or hesperidin (200 mg/kg/day, orally for 14 days). Blood urea, serum creatinine, albumin, cystatin-C (CYS-C), myeloperoxidase (MPO), and glucose were measured. The renal malondialdehyde (MDA), glutathione (GSH), catalase, and SOD were estimated. Renal TNF-α protein expression was evaluated. Histopathological examination and immunostaining study of Bax, Nrf-2, and NF-κB were performed. Sitagliptin or hesperidin attenuated CsA-mediated elevations of blood urea, serum creatinine, CYS-C, glucose, renal MDA, and MPO, and preserved the serum albumin, renal catalase, SOD, and GSH. They reduced the expressions of TNF-α, Bax, NF-κB, and pathological kidney damage. Nrf2 expression in the kidney was raised. Hesperidin or sitagliptin could protect the kidney against CsA through the mitigation of oxidative stress, apoptosis, and inflammation. Sitagliptin proved to be more beneficial than hesperidin.

Preventive effects of hesperidin in an experimental model ofs acute lung inflammation.

In this study, we hypothesized that long-term administration of hesperidin can modulate the inflammatory response and oxidative stress in animals submitted to mechanical ventilation (MV). Twenty-five C57BL/6 male mice were divided into 5 groups: control, MV, animals receiving hesperidin in three doses 10, 25 and 50 mg/kg. The animals received the doses of hesperidin for 30 days via orogastric gavage, and at the end of the period the animals were submitted to MV. In animals submitted to MV, increased lymphocyte, neutrophil and monocyte/macrophage cell counts were observed in the blood and airways. Associated to this, MV promoted an increase in inflammatory cytokine levels such as CCL2, IL-12 and TNFα. The daily administration of hesperidin in the three doses prevented the effects caused by MV, which was observed by a lower influx of inflammatory cells into the airways, a reduction in inflammatory markers and less oxidative damage.

Iron overload induced submandibular glands toxicity in gamma irradiated rats with possible mitigation by hesperidin and rutin.

BACKGROUND: Radiation triggers salivary gland damage and excess iron accumulates in tissues induces cell injury. Flavonoids are found in some fruits and are utilized as potent antioxidants and radioprotective agents. This study aimed to evaluate the antioxidant and anti-inflammatory effects of hesperidin and rutin on gamma radiation and iron overload induced submandibular gland (SMG) damage and to evaluate their possible impact on mitigating the alteration in mTOR signaling pathway and angiogenesis. METHODS: Forty-eight adult male Wistar albino rats were randomly assigned to six groups: group C received a standard diet and distilled water; group H received hesperidin at a dose of 100 mg/kg; four times a week for four weeks; group U received rutin at a dose of 50 mg/kg; three times a week for three weeks; group RF received a single dose (5 Gy) of gamma radiation followed by iron at a dose of 100 mg/kg; five times a week for four weeks; group RFH received radiation and iron as group RF and hesperidin as group H; group RFU received radiation and iron as group RF and rutin as group U. SMG specimens from all groups were removed at the end of the experiment; and some were used for biochemical analysis, while others were fixed for histological and immunohistochemical examination. RESULTS: In the RF group, several genes related to antioxidants (Nrf-2 and SOD) and DNA damage (BRCA1) were significantly downregulated, while several genes related to inflammation and angiogenesis (TNFα, IL-1ß and VEGF) and the mTOR signaling pathway (PIK3ca, AKT and mTOR) were significantly upregulated. Acinar cytoplasmic vacuolation, nuclear pyknosis, and interacinar hemorrhage with distinct interacinar spaces were observed as histopathological changes in SMGs. The duct system suffered significant damage, eventually degenerating entirely as the cells were shed into the lumina. VEGF and NF-κB were also significantly overexpressed. Hesperidin and rutin cotreatment generated partial recovery as indicated by significant upregulation of Nrf-2, SOD and BRCA1 and considerable downregulation of TNF-α, IL-1ß, VEGF, PIK3ca, AKT, and mTOR. Although some acini and ducts continued to deteriorate, most of them had a normal appearance. There was a notable decrease in the expression of VEGF and NF-κB. CONCLUSIONS: In γ-irradiated rats with iron overload, the administration of hesperidin and rutin may mitigate salivary gland damage.

Synergistic effects of bee venom, hesperidin, and piperine with tamoxifen on apoptotic and angiogenesis biomarker molecules against xerographic MCF-7 injected rats.

Breast cancer ranks as the second leading most significant of mortality for women. Studies have demonstrated the potential benefits of natural compounds in cancer treatment and prevention, either in isolation or in conjunction with chemotherapy. In order to improve Tamoxifen's therapeutic efficacy in in-vivo studies, our research sought to determine the effects of hesperidin, piperine, and bee venom as natural compounds, as well as their combination effect with or without Tamoxifen. First, 132 female albino rats were equally divided into six groups and five subgroups, and breast cancer was induced in the selected groups by xenografting of MCF7 cells. Second, the effect of single and best ratio combinations treatment from previous in vitro studies were selected. Next, tumorous mammary glands were collected for apoptotic and antiapoptotic biomarkers and cell cycle analysis. Single or combined natural products with or without Tamoxifen revealed a significant up-regulation in apoptotic genes Bax and Casp3 and a downregulation of antiapoptotic and angiogenesis genes Bcl-2 and VEGF genes. We found that cell cycle arrest in the G0/G1 phase was exclusively caused by Tamoxifen and/ or hesperidin. However, the cell cycle arrest in the G2/M phase is a result of the combination of piperine and bee venom, with or without Tamoxifen by using the flow cytometric technique. Our research concludes that bee venom, hesperidin, and piperine can synergistically enhance to increase Tamoxifen's efficiency in the management of breast cancer.

Protective role of hesperetin in sorafenib-induced hepato- and neurotoxicity in mice via modulating apoptotic pathways and mitochondrial reprogramming.

INTRODUCTION: Sorafenib, an FDA-approved standard chemotherapy for advanced hepatocellular carcinoma, is associated with numerous adverse effects that significantly impact patients' physiological well-being. Consequently, identifying agents that mitigate these side effects while enhancing efficacy is crucial. Hesperetin, a flavone present in fruits and vegetables, possesses antioxidant, anti-inflammatory, and anti-cancer properties. This study aimed to investigate the hepatotoxic and neurotoxic effects of sorafenib and the potential protective role of hesperetin. MATERIALS AND METHODS: Swiss albino mice were orally administered sorafenib (100 mg/kg) alone or in combination with hesperetin (50 mg/kg) over 21 days. Behavioral assessments for anxiety and depressive-like behaviors were conducted. Additionally, evaluations encompassed apoptotic activity, mitochondrial integrity, liver enzyme levels, proliferation rates, and histopathological changes. RESULTS: Combining hesperetin with sorafenib showed improvements in behavioral alterations, liver damage, brain mitochondrial dysfunction, and liver apoptosis compared to the sorafenib-only group in mice. CONCLUSION: Hesperetin exhibits potential as an adjunct to sorafenib, mitigating its side effects by attenuating its toxicity, enhancing efficacy, and potentially reducing the occurrence of sorafenib-induced resistance through the downregulation of hepatocyte growth factor levels.

Neuroprotective Potential of Hesperidin as Therapeutic Agent in the Treatment of Brain Disorders: Preclinical Evidence-based Review.

Neurodegenerative disorders (NDs) are progressive morbidities that represent a serious health issue in the aging world population. There is a contemporary upsurge in worldwide interest in the area of traditional remedies and phytomedicines are widely accepted by researchers due to their health-promoted effects and fewer side effects. Hesperidin, a flavanone glycoside present in the peels of citrus fruits, possesses various biological activities including anti-inflammatory and antioxidant actions. In various preclinical studies, hesperidin has provided significant protective actions in a variety of brain disorders such as Alzheimer's disease, epilepsy, Parkinson's disease, multiple sclerosis, depression, neuropathic pain, etc. as well as their underlying mechanisms. The findings indicate that the neuroprotective effects of hesperidin are mediated by modulating antioxidant defence activities and neural growth factors, diminishing apoptotic and neuro-inflammatory pathways. This review focuses on the potential role of hesperidin in managing and treating diverse brain disorders.

Hesperidin improves physiological outcomes in an arginine vasopressin rat model of pre-eclampsia.

BACKGROUND: Hesperidin, a flavanone commonly found in citrus fruits and herbal formulations, has emerged as a potential new therapeutic agent for modulating several diseases. Since pre-eclampsia is a growing public health threat, it may negatively impact the economy and increase the disease burden of South Africa. Phytocompounds are easily accessible, demonstrate minimal side effects, and may confer novel medicinal options as a treatment and preventive preference. OBJECTIVE: To investigate the physiological, biochemical, and hematological outcomes of hesperidin in an arginine vasopressin (AVP)-induced rodent model of pre-eclampsia. METHODS: Female Sprague-Dawley rats were surgically implanted with mini-osmotic pumps to deliver AVP (200 ng/h) subcutaneously. Animals were treated with hesperidin at 200 mg/kg.b.w via oral gavage for 14 days. Systolic and diastolic blood pressures were measured on GD 7, 14, and 18 using a non-invasive tail-cuff method and were euthanized on GD 21. RESULTS: The findings showed that hesperidin administration significantly decreased blood pressure (P < 0.05) and urinary protein levels in pregnant rats (P < 0.001). Placental and individual pup weight also increased significantly in the pregnant hesperidin-treated groups compared to AVP untreated groups (P < 0.001). Biochemical and hematological markers such as white blood cell count and lymphocyte levels differed significantly (P < 0.05) in AVP groups treated with and without hesperidin. CONCLUSION: Our results suggest that hesperidin is an antihypertensive agent with modes of action associated with its diuretic and blood pressure lowering effects and reduction of proteinuria in AVP-induced pre-eclamptic rats.

Hesperidin counteracts chlorpyrifos-induced neurotoxicity by regulating oxidative stress, inflammation, and apoptosis in rats.

Chlorpyrifos (CPF), considered one of the most potent organophosphates, causes a variety of human disorders including neurotoxicity. The current study was designed to evaluate the efficacy of hesperidin (HSP) in ameliorating CPF-induced neurotoxicity in rats. In the study, rats were treated with HSP (orally, 50 and 100 mg/kg) 30 min after giving CPF (orally, 6.75 mg/kg) for 28 consecutive days. Molecular, biochemical, and histological methods were used to investigate cholinergic enzymes, oxidative stress, inflammation, and apoptosis in the brain tissue. CPF intoxication resulted in inhibition of acetylcholinesterase (AChE) and butrylcholinesterase (BChE) enzymes, reduced antioxidant status [superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione (GSH)], and elevation of malondialdehyde (MDA) levels and carbonic anhydrase (CA) activities. CPF increased histopathological changes and immunohistochemical expressions of 8-OHdG in brain tissue. CPF also increased levels of glial fibrillary acidic protein (GFAP) and nuclear factor kappa B (NF-κB) while decreased levels of nuclear factor erythroid 2-related factor 2 (Nrf-2), heme oxygenase-1 (HO-1) and peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α). Furthermore, CPF increased mRNA transcript levels of caspase-3, Bax, PARP-1, and VEGF, which are associated with apoptosis and endothelial damage in rat brain tissues. HSP treatment was found to protect brain tissue by reducing CPF-induced neurotoxicity. Overall, this study supports that HSP can be used to reduce CPF-induced neurotoxicity.

Naringenin, Hesperidin and Quercetin Ameliorate Radiation-Induced Damage In Rats: In Vivo And In Silico Evaluations.

In this study, we sought to determine how well naringenin, hesperidin, and quercetin prevented damage brought on by radiotherapy. During the investigation, 48 adult female Sprague Dawley rats were used. Eight groups of eight rats each were formed by randomly assigning the rats to the groups. The normal control group was represented by Group 1. Group 2 rats were those that received a dose of 15 Gray (Gy) of radiotherapy. The rats assigned to Group 3 received only Naringenin, whereas those assigned to Group 4 received only quercetine, and those assigned to Group 5 received only hesperidin. Rats in Group 6, 7 and 8 were received naringenin, quarcetin and hesperidin at a dose of 50 mg/kg daily for one week prior to radiotheraphy exposition. After radiotheraphy and phenolic compounds rats were sacrificed and some metabolic enzyme (aldose reductase (AR), sorbitol dehydrogenase (SDH), paraoxonase-1 (PON1), butyrylcholinesterase (BChE) and glutathione S-transferase (GST)) activity was determined in eye and brain tissues. It was found that phenolic compounds have protective effect against radiation-induced damage because of their anti-diabetic antioxidant and anti-inflammatory properties. In addition, hesperidin was found to be superior to quercetin and naringenin in terms of enzyme activity efficacy. Furthermore, hesperidin exhibited favorable binding affinity for BChE in silico compared to other enzymes.

Hesperidin suppressed metastasis, angiogenesis and tumour growth in Balb/c mice model of breast cancer.

Considering the unfavourable response of breast cancer (BC) to treatment, we assessed the therapeutic potential hesperidin in mice bearing 4T1 BC tumours. Anti-tumour effects were assessed by measuring pathologic complete response (pCR), survival analysis, immunohistochemistry for E-cadherin, VEGF, MMP9, MMP2 and Ki-67, serum measurement of IFNγ and IL-4, and gene expression analysis of CD105, VEGFa, VEGFR2 and COX2. Survival of tumour-bearing mice was the highest in mice receiving a combination of hesperidin and doxorubicin (Dox) (80%) compared to the normal saline (43%), hesperidin 5 (54%), 10 (55.5%), 10 (60.5%) and 40 (66%) mg/kg, and 10 mg/kg Dox-treated (73%) groups (p < 0.0001 for all). Compared to the normal saline group, there was a significant elevation in IFNγ level in the animals receiving 20 (p = 0.0026) and 40 (p < 0.001) mg/kg hesperidin, 10 mg/kg Dox (p < 0.001), and combined hesperidin (20 mg/kg) and Dox (10 mg/kg) (p < 0.001). A significant reduction in the gene expression of CD 105 (p = 0.0106), VEGFa (p < 0.0001), VEGFR2 (p < 0.0001), and Cox2 (p = 0.034) and a significant higher pCR score (p = 0.006) were noticed in mice treated with 10 mg/kg Dox + 20 mg/kg hesperidin compared to those treated with 10 mg/kg Dox alone. Immunohistochemical staining showed significant reductions in Ki-67 (p < 0.001) and VEGF (p < 0.001) and a significant elevation in E-cadherin (p = 0.005) in the 10 mg/kg Dox + 20 mg/kg treatment group than in 10 mg/kg Dox alone group. Hesperidin can be considered as a potentially suitable anti-cancer agent for BC that can synergize with other chemotherapeutics.

Oral phytochemicals as photoprotectants in UVR exposed hairless mice: A study of hesperidin methyl chalcone, phloroglucinol, and syringic acid.

Ultraviolet radiation is the primary risk factor for keratinocyte carcinoma. Because of increasing incidence rates, new methods of photoprotection must be explored. Oral supplementation with photoprotective compounds presents a promising alternative. Phytochemical compounds like hesperidin methyl chalcone, phloroglucinol, and syringic acid are particularly of interest because of their antioxidant properties. Our primary outcome was to evaluate the effects of oral phytochemicals on photocarcinogenesis with time until tumour onset as the primary endpoint. A total of 125 hairless C3.Cg-Hrhr/TifBom Tac mice were randomised to receive tap water supplemented with either 100 mg/kg hesperidin methyl chalcone, phloroglucinol, or syringic acid, 600 mg/kg nicotinamide as a positive control, or no supplementation. The mice were irradiated with 3.5 standard erythema doses thrice weekly to induce photocarcinogenesis. Supplementation with the phytochemicals phloroglucinol and syringic acid and nicotinamide delayed tumour onset from a median of 140 days to 151 (p = 0.036), 157 days (p = 0.02), and 178 (p = 2.7·10-5), respectively. Phloroglucinol and nicotinamide supplementation reduced tumour number. Nicotinamide increased UV-induced pigmentation and reduced oedema formation, while phloroglucinol supplementation reduced epidermal thickness. These results indicate that oral supplementation with phloroglucinol and syringic acid protects against photocarcinogenesis in hairless mice, but not to the same extent as nicotinamide.